Methods of Making and Using Filtering Unit for a Virucide Substance

ABSTRACT

A filtering unit for removing a virucidal substance from a biological fluid including an outer casing having at least one input aperture and at least one output aperture. The outer casing including a filter medium, which separates the filtration unit into an input compartment and an output compartment. The filter medium includes at least one hydrophilic material able to absorb or adsorb the virucidal substance. The at least one hydrophilic material includes either porous non-woven material or a porous membrane.

The invention relates to a filtration unit intended to remove avirucidal substance present in a biological fluid.

It typically applies to the case where the virucidal substance haspreviously been added to a biological fluid, in particular blood plasma,intended to be transfused into a patient. The aim of this addition is tosubject the biological fluid to a viral inactivation treatment prior toits transfusion into the patient, so as to inactivate any virusesinfecting the biological fluid.

A conventional technique for viral inactivation of plasma uses acolouring substance as a virucidal substance, for example methylene blueor one of its derivatives.

The principle of this technique is based on photochemical reactionsbetween the colouring substance and the viral DNA or RNA which may bepresent in the biological fluid.

Exposure of the colouring substance to light brings about aphotochemical reaction which transmits energy to the DNA and RNAmolecules so that the virus is inactivated.

During these photochemical reactions, the colouring substance is notremoved so that it remains in the biological fluid after exposure tolight.

After the use of this viral inactivation technique, a very small amountof the colouring substance may be left in the biological fluid and thusbe transfused into the patient at the same time as the biological fluid.

However, recent studies seem to show the possible toxicity of certaincolouring substances used, and in particular methylene blue, when theyare injected into the patient.

So much so that many countries are demanding the systematic removal ofcolouring substances prior to injection of the biological fluid into thepatient.

The invention therefore aims to propose a filtration unit which makes itpossible to remove substantially all the virucidal substance present inthe biological fluid while leaving the composition of the biologicalfluid substantially unchanged during the filtration.

To that end, the object of the invention is a filtration unit intendedto remove a virucidal substance present in a biological fluid,comprising an outer casing provided with at least one input aperture andat least one output aperture, the casing containing a filter mediumwhich delimits two compartments, respectively input and output, of thefiltration unit, in which the filter medium is produced from at leastone hydrophilic material in the form of a porous non-woven materialand/or a porous membrane capable of absorbing and/or adsorbing thevirucidal substance.

According to one embodiment, the mean porosity of the filter medium isdefined so that the contact area between the biological fluid and thefilter medium is sufficient to remove substantially all the virucidalsubstance while leaving the composition of the biological fluidsubstantially unchanged during its passage through the filter medium,namely being between 1 μm and 15 μm.

In a variant, the mean diameter of the fibres of the porous non-wovenmaterial is between 0.5 μm and 5 μm.

The input compartment and/or the output compartment communicate with theoutside of the filtration unit by means of an input, respectivelyoutput, tube.

The hydrophilic material of the filter medium is chosen in particularfrom amongst the naturally hydrophilic materials or the materials, inparticular based on plastic material, made hydrophilic, for example fromamongst the polymers and/or the copolymers based on polyester,acrylonitrile or polyvinylidene fluoride.

According to one embodiment, the filter medium comprises a number oflayers of hydrophilic material, identical or different in nature to oneanother, with a contact area identical or different to one another.

The filter medium has for example a thickness between 1 and 10millimetres.

According to one embodiment, the outer casing of the filtration unit isrigid.

According to another embodiment, the outer casing of the filtration unitis flexible.

FIG. 3 depicts, in top view and transverse section, the embodiment ofFIG. 1, showing in particular the assembly of the frame containing thefilter medium in the outer casing.

FIG. 4 depicts, in front view and partial longitudinal section, thefiltration unit of FIG. 3 in which the spacing rods appear.

A filtration unit 1 intended to remove a virucidal substance present ina biological fluid comprises typically an outer casing 2 provided withat least one input aperture 3 and at least one output aperture 4, thecasing containing a filter medium 5 which delimits two compartments,respectively input 6 and output 7, of the filtration unit 1.

In the description, the words “input” and “output” are defined withrespect to the direction of movement of the biological fluid in thefiltration unit 1 (see the arrows shown in FIG. 1).

According to one particular embodiment, the biological fluid is blood ora blood compound, in particular blood plasma, and the virucidalsubstance is methylene blue or one of its derivatives.

Prior to its passage into the filtration unit 1, the biological fluidhas undergone a viral inactivation treatment by means of the virucidalsubstance which was added to the biological fluid.

This treatment, generally used at the blood transfusion centre, will notbe described further here.

The filtration unit 1 is intended to be integrated, in particular bymeans of tubes, respectively input 8 and output 9, into a systemcomprising for example bags for medical use, tubes, clamps or otherfilters (for example to remove leukocytes from the biological fluid).

In such a system, the filtration unit 1 is disposed on the flow path ofthe biological fluid so that the biological fluid with the virucidalsubstance added enters the filtration unit 1 by the input aperture 3 andthe biological fluid free from the virucidal substance is delivered bymeans of the output aperture 4.

One particular example of such a system is a transfusion line of a bagcontaining a biological fluid to be transfused into a patient. In such aline, the filtration unit 1 is connected by its input 3 to the bagcontaining the biological fluid with the virucidal substance added andby its output 4 to means of transfusion of the biological fluid freefrom virucidal substance.

These various systems are not described further inasmuch as theycomprise the filtration unit 1 according to the structure describedhere.

A description is now given of a first embodiment of the filtration unit1 comprising a flexible outer casing 2 formed by the assembly of twosheets of flexible plastic material 10, 11 connected to one another, forexample by welding, on their periphery (FIG. 1).

This outer casing contains a filter medium designated generally by thereference 5, the structure of which will be described in more detailbelow.

The filter medium 5 is held in a flexible and impervious support frame12 and delimits two compartments, respectively input 6 and output 7, ofthe filtration unit 1.

The input compartment 6 communicates with the outside of the filtrationunit 1 by means of an input tube 8 which is used to fill it with thebiological fluid with the virucidal substance added.

The output compartment 7 communicates with the outside of the filtrationunit 1 by means of an output tube 9 which delivers the biological fluidfree from virucidal substance.

The structure of the filtration unit 1 thus allows the biological fluidwith the virucidal substance added to be received in the inputcompartment 6 via the input aperture 3, to pass through the filtermedium 5 so that the virucidal substance is absorbed and/or adsorbedthereby, and then the biological fluid free from virucidal substance isreceived in the output compartment 7 in order to be delivered via theoutput aperture 4.

According to one embodiment, the input tubes 8 and/or output tubes 9 areflexible, and can be cut and welded.

Where a collecting bag is associated with the output tube 9, thisembodiment makes it possible, after separation of the filtration unit 1by cutting and welding of the output tube 9, to obtain a bag full ofbiological fluid free from virucidal substance. Such a bag can then beused conventionally, for example for transfusion into a patient.

A first level of sealing of the filtration unit 1 is provided betweenthe filter medium 5 and the flexible frame 12 where no tube passes.

A second level of sealing is provided at the periphery of the filtrationunit 1 where the two outer sheets 10, 11, the periphery of the flexibleframe 12 and the passage of the input tube 8 and output tube 9 cometogether.

This second level of sealing can be provided by the known techniques forconnecting plastic materials, for example by high-frequency welding.

The implementation of the assembly of the filtration unit 1 is nowdescribed with reference to FIGS. 2 to 4.

The flexible frame 12 is formed by an assembly of two sheets 13, 14, forexample plasticised sheets, between which the filter medium 5 is placed.

These two sheets 13, 14 are perforated in their central part and eachhave at least one opening 15, 16 allowing passage of the biologicalfluid to be filtered.

The two sheets 13, 14 are fixed to one another preferably in the regionof the periphery of the filter medium 5, for example by a weld seam 17,made through the filter medium 5, providing both the fixing of thefilter medium 5 and also the sealing of the unit 1.

The welding of the sheets 13, 14 through the filter medium 5 causes acompression 18, forming an impervious seam around the filter medium 5.

The periphery 19 of the flexible frame 12 is also welded with the outersheets 10, 11 forming the outer casing 2 of the filtration unit 1, thesebeing welded to one another over their entire circumference and in theregion of their periphery, thus providing the sealing of the unit 1.

In order to avoid the filter medium 5 sticking against the outer casing2, and thus interfering with the flow of the biological fluid into theoutput compartment 7, two spacing rods 20, 21 are placed inside theoutput compartment 7, between the filter medium 5 and the outer casing2.

These two rods 20, 21 keep the output compartment 7 clear of the filtermedium 5 and thus avoid the filter medium 5 being flattened against theinner wall of the outer sheet 2.

The rods 20, 21 can be produced from flexible tubes welded for exampleat the inner wall of the sheet of the outer casing 2, for example in theregion of the peripheral weld 19 of the filtration unit 1.

It is self-evident that the number of spacing rods can vary, dependingfor example on the dimensions of the filtration unit 1.

For example, provision of a single spacing rod folded so as to form aloop inside the output compartment 7 can be envisaged.

Preferably, flexible rods are used, in order not to interfere with thepossibilities of folding the filtration unit 1.

In a second embodiment (not depicted), the filtration unit 1 comprises arigid outer casing 2, for example made of a rigid plastic material suchas polycarbonate.

There will now be described in more detail the structure andimplementation of the filter medium 5 capable of removing substantiallyall the virucidal substance while leaving the composition of thebiological fluid substantially unchanged during the filtration.

In a first embodiment, the filter medium 5 is produced from at least onehydrophilic material in the form of a porous non-woven material.

In a second embodiment, the filter medium 5 is produced from at leastone hydrophilic material in the form of a porous membrane.

In a third embodiment, the filter medium 5 is produced from ahydrophilic material in the form of at least one porous membrane whichis inserted between a number of layers of hydrophilic material in theform of a non-woven material.

In these three embodiments, the hydrophilic material is capable ofabsorbing and/or adsorbing the virucidal substance, in particular byaffinity between the virucidal substance and the hydrophilic material.

Various materials can be used for producing the filter medium dependingon the nature of the fluid to be filtered and that of the biologicalfluid.

The choice of materials usable in the filtration unit according to theinvention is however limited by the fact that they must not prevent, inparticular by affinity, the passage of the cellular or non-cellularconstituents of the biological fluid.

In other words, the material forming the filter medium must be capableof absorbing and/or adsorbing the virucidal substance but not theconstituents of the biological fluid.

In the case of treatment of a blood plasma containing methylene blue,the following can be cited amongst the possible materials: the polymersand/or the copolymers based on polyester, acrylonitrile orpolyvinylidene fluoride.

These polymeric products are generally not naturally hydrophilic andmust be treated by physical and/or chemical methods, in order to givethem said hydrophilic properties.

These treatments consist for example in grafting hydrophilicsubstituents, for example hydroxyl or carboxylic type groups, onto thepolymer, according to known methods.

Such polymers made hydrophilic by physical and/or chemical treatment areavailable on the market.

The hydrophilic nature of the material forming the filter medium 5allows a good wettability of the filter medium during passage of thebiological fluid, which allows in particular a better flow of thebiological fluid through the filtration unit 1 but also an improvementin the filtration efficiency.

The porosity characteristics of the filter medium allow the passage ofthe biological fluid through the filtration unit while leaving thecomposition of the biological fluid substantially unchanged.

To that end, the mean size of the pores of the filter medium is chosenaccording to the biological fluid to be treated. For example, for thefiltration unit 1 to allow the constituents of whole blood to pass, themean size of the pores can be of the order of or greater than 7 μm. Inthe case of blood plasma, the mean size of the pores can be smaller, forexample of the order of 4 μm, on account of the absence of cellularconstituents in the plasma.

During passage of the biological fluid with the virucidal substanceadded through the filter medium 5, the contact area between thebiological fluid and the filter medium must be sufficient to removesubstantially all the virucidal substance while leaving the compositionof the biological fluid substantially unchanged.

In the first embodiment, this characteristic is advantageously obtainedby means of the use of a non-woven material which has, through itsstructure, a large contact area for a small volume.

Contact area between the biological fluid and the filter medium meansthe area over which the absorption and/or adsorption of the virucidalsubstance by the porous material can take place. It is self-evident thatthis area is a function in particular of the area of the filter medium,its porosity, its thickness and the diameter of the fibres of thenon-woven material.

Thus, by changing the diameter of the fibres, the porosity of thenon-woven material and the thickness of the filter medium 5 it composes,access can be obtained to a wide range of contact areas which makes itpossible to remove substantially all the virucidal substance whileleaving the composition of the biological fluid substantially unchanged.

By way of example, there can be cited a filter medium 5 formed from anon-woven material made of polyester having a thickness of the order of5 mm, a mean porosity of the order of 8 μm and a mean fibre diameter ofthe order of 2 μm, allowing the removal of a concentration of 1 μM ofmethylene blue in 250 ml of blood plasma.

It should be noted however that these values can vary to a great extent,in particular according to the time of contact between the filter mediumand the biological fluid, that is to say the filtration speed.

In the second embodiment, a porous membrane is used as the filter medium5 to absorb and/or adsorb the virucidal substance present in thebiological fluid.

In one particular example, such a membrane is made of polyvinylidenefluoride and with a pore size calibrated to a value between 1 and 15 μm.

In the third embodiment, the filter medium 5 can combine the twomaterials used in the preceding embodiments, namely comprise a number oflayers of hydrophilic material in the form of a porous non-wovenmaterial and one or more porous membranes. The material and/or thestructure of the material forming these layers can then be identical ordifferent to one another.

The layers are then disposed, for example contiguously, next to oneanother in the filtration unit so that the biological fluid passesthrough them successively during the filtration.

In one particular example, there can be cited a filter medium 5 formedfrom a superposition of layers formed respectively of a “spunbond” typepolyester non-woven material, a “meltblown” type polyester non-wovenmaterial, one or more polyvinylidene fluoride membranes, a “meltblown”type polyester non-woven material and a “spunbond” type polyesternon-woven material.

The words “spunbond” and “meltblown” mean two of the conventionalmethods of forming a layer of non-woven material directly from thepolymer, namely respectively either by forming continuous monofilamentsor by blowing the polymer in the molten state into irregular filaments.

As these techniques are conventional, they will not be detailed furtherhere.

In this embodiment, the two outer layers of “spunbond” non-wovenmaterial are identical and serve respectively as a pre- and post-filter.Furthermore, they have the function of improving the weldability of thefilter medium 5 onto the casing 2 of the filtration unit 1.

The two layers of “meltblown” non-woven material and the membrane ormembranes placed between them form more particularly the filter medium 5capable of absorbing and/or adsorbing the virucidal substance.

Furthermore, the two layers of “meltblown” non-woven material areidentical and have the function of protecting the membrane or membranes.

1-20. (canceled)
 21. A method for eliminating a virucidal substance froma biological fluid comprising: passing the biological fluid through afilter medium produced from a treate, hydrophilic polymer or copolymercapable of absorbing or adsorbing the virucidal substance and having aporosity that allows passage of the biological fluid through the filtermedium; wherein the polymer or copolymer comprises polyester,acrylonitrile, or polyvinylidene fluoride.
 22. The method according toclaim 21, wherein the biological fluid comprises blood, serum or plasma.23. The method according to claim 21, wherein the virucidal substancecomprises methylene blue.
 24. The method according to claim 22, whereinthe methylene blue has a concentration of 1 μM.
 25. The method accordingto claim 21, wherein the treated, hydrophilic polymer or copolymercomprises treated, hydrophilic polyester.
 26. The method according toclaim 21, wherein the treated, hydrophilic polymer or copolymercomprises treated, hydrophilic acrylonitrile.
 27. The method accordingto claim 21, wherein the treated, hydrophilic polymer or copolymercomprises treated, hydrophilic polyvinylidene fluoride.
 28. A method offorming a filter medium comprising: treating a polymer or copolymer torender it hydrophilic and capable of absorbing or adsorbing a virucidalsubstance, said polymer or copolymer comprising polyester, acrylonitrileor polyvinylidene fluoride; and forming a filter medium containing thepolymer or copolymer, wherein the filter medium has a mean porosity ofbetween 1 μm and 15 μm.
 29. The method according to claim 28, whereintreating comprises grafting a hydrophilic substituent to the polymer orcopolymer to render it hydrophilic and capable of absorbing or adsorbinga virucidal substance.
 30. The method according to claim 29, wherein thehydrophilic substituent comprises a hydroxyl or a carboxylic group. 31.(canceled)
 32. A method of forming a filtration unit comprising:treating a polymer or copolymer to render it hydrophilic and capable ofabsorbing or adsorbing a virucidal substance, said polymer or copolymercomprising polyester, acrylonitrile or polyvinylidene fluoride; forminga filter medium containing the polymer or coplymer, wherein the filtermedium has a mean porosity of between 1 μm and 15 μm; placing the filtermedium in a casing having an inlet aperture and an outlet aperture toform a filtration unit.
 33. The method according to claim 32 whereintreating comprises grafting a hydrophilic substituent to the polymer orcopolymer to render it hydrophilic and capable of absorbing or adsorbinga virucidal substance.
 34. The method according to claim 33, wherein thehydrophilic substituent comprises a hydroxyl or a carboxylic group. 35.The method according to claim 32, wherein the polymer or copolymercomprises polyester.
 36. The method according to claim 32, wherein thepolymer or copolymer comprises acrylonitrile.
 37. The method accordingto claim 32, wherein the polymer or coplymer comprises polyvinylidenefluoride.
 38. The method according to claim 32, wherein the filtermedium has a thickness between 1 and 10 millimeters.
 39. The methodaccording to claim 32, wherein the filter medium comprises non-wovenfibers having a mean diameter of between 0.5 μm and 5 μm.
 40. The methodaccording to claim 32, wherein the casing comprises an inlet apertureand an outlet aperture.
 41. The method according to claim 21, whereinthe filter medium has a mean porosity of between 1 μm and 15 μm.
 42. Themethod according to claim 21, wherein the treated, hydrophilic polymeror copolymer is in the form or a membrane.
 43. The method according toclaim 21, wherein the treated, hydrophilic polymer or copolymer is inthe form of non-woven fibers.
 44. The method according to claim 21,wherein the treated, hydrophilic polymer or copolymer is in the form ofa porous non-woven material and one or more porous membranes.